The pathogenesis of feline leukemia virus (FeLV) infection is initiated in all cats by viral infection of circulating and tissue lymphocytes within days after exposure. Subsequent development of self-limiting (regressive) versus leukemogenic (progressive) infection depends upon early host containment of FeLV-infected cells in lymphoid and hemopoietic tissues prior to the phases of polyclonal hemopoietic cell infection, persistent viremia, and epithelial dissemination. The autologous resistance of cats to FeLV is age-related, macrophage-associated, and can be modulated by treatments which impair lymphoreticular function (i.e. methyl prednisolone (MP) or silica). In preleukemic cats, FeLV (Rickard strain) replicates continuously in lymphoid B-cell regions, and in marrow neutrophilic myelocytes and megakaryocytes and in mucosal epithelium, but subsequently transforms T lymphocytes in the thymus and elsewhere. The objectives of this proposal are to extend the above investigations of FeLV leukemogenesis by combining in vitro lymphocyte culture techniques with prospective study of controlled FeLV infections in SPF cats to examine the early and late interactions of FeLV with target lymphocyte subpopulations and to investigate the host lymphocyte-and macrophage-mediated restriction of FeLV-infected autologous lymphocytes in both transiently infected and preleukemic cats. The specific tropisms of FeLV for feline lymphocyte subsets and the nature of the resultant infection (i.e., productive versus nonproductive or latent) will be evaluated. The influence of substances and conditions which may act as promoters of infection or transformation of lymphoid cells by FeLV (e.g., lymphocyte mitogens, phorbol esters) will also be studied in vitro and in vivo. The presence of latently infected lymphoid cells in cats which have experienced self-limiting FeLV infection will be investigated by treatment of these animals and their cultured lymphocytes with substances which enhance FeLV susceptibility or expression (e.g., MP, TPA). The thrust of this proposal therefore, is to examine in a naturally occurring and experimentally reproducible model of viral leukemogenesis the interplay between retravirus and the lymphoreticular cells which serve as both targets for viral replication and oncogenesis, and effectors for containment of virus infected and transformed cells.